Brentuximab Vedotin in Combination with Nivolumab, Doxorubucin, and Dacarbazine in Newly Diagnosed Patients with Advanced Stage Hodgkin Lymphoma

Background For patients with advanced classical Hodgkin lymphoma (cHL), the most common frontline regimen has historically consisted of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), which originated in 1975 (Connors 2018). However, up to 30% of patients treated with ABVD as frontline therapy will relapse or are refractory to treatment (Canellos 1992; Carde 2016; Gordon 2013). Additionally, bleomycin is associated with potentially fatal pulmonary toxicity (Canellos 2004; Martin 2004), and vinblastine is associated with neutropenia and peripheral neuropathy. Brentuximab vedotin (BV, ADCETRIS®) has been approved for the treatment of adult patients with previously untreated Stage III or IV cHL in combination with doxorubicin, vinblastine, and dacarbazine based on the results of the ECHELON-1 study (Connors 2017). Data reported from ECHELON-1 showed patients randomized to the BV + doxorubicin, vinblastine, and dacarbazine (A + AVD) treatment arm had a statistically significant 23% risk reduction in modified PFS events vs patients randomized to the ABVD arm of the study. The combination of BV plus nivolumab was reported as showing potential for the treatment of cHL. The combination was evaluated as a potential frontline treatment option for patients with cHL who are over 60 years of age and ineligible for or declining conventional combination chemotherapy (Friedberg, 2018). The ongoing study reported an ORR of 82% in 11 patients and the regimen appears well tolerated in this population. In another trial in 62 patients in the first salvage setting, the combination produced a 61% CR rate (Herrera 2018) and the patients were able to undergo subsequent stem cell transplant. BV and nivolumab have been combined separately with doxorubicin, vinblastine, and dacarbazine and shown to be active and well tolerated. Furthermore, BV has been evaluated in combination with just doxorubicin and dacarbazine, omitting vinblastine, in 34 patients with previously untreated non-bulky stage I/II cHL and showed 100% complete response rate at end of treatment (EOT) and PFS and OS rates of 100% at last follow up (median=15 months; Abramson 2018). This combination resulted in a low incidence of neutropenia and alopecia, and moderate (Grade 1 or 2) peripheral neuropathy. It is therefore reasonable to expect that the combination of BV, nivolumab, doxorubicin, and dacarbazine (AN + AD) will result in high response rates and be well tolerated, with potentially less toxicity. S